Increased expression of glycinamide ribonucleotide transformylase is associated with a poor prognosis in hepatocellular carcinoma, and it promotes liver cancer cell proliferation

Xia, Cong; Lu, Cuihua; Huang, Xiaodong; Yang, Dayu; Cui, Xiaopeng; Cai, Jing; Lv, Liting; He, Song; Zhang, Yixin; Ni, Runzhou

doi:10.1016/j.humpath.2013.11.021

Cited by 25 publications

(14 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Among the upregulated OCM genes were CBS and CTH , which participate in the conversion of Hcy to cysteine, removing Hcy from the methylation cycle [ 15 ], MTRR , and GART (Table 1 ; Additional file 1 : Table S1; Additional file 2 : Figures S1 and S3). GART is an element of the purine biosynthetic pathway, and its increased expression may predict poor outcome in glioma and hepatocellular carcinoma [ 82 , 83 ]. This suggests that GART may be examined as a potential target in drug combinations that include 5-azacytidine, in order to enhance the treatment effect by using an additional agent that would suppress purine biosynthesis (Additional file 1 : Table S1).…”

Section: Resultsmentioning

confidence: 99%

“…2d ; Additional file 2 : Figures S4D, S13 and S14), suggesting that treatment with paclitaxel may inhibit reactions that involve folate intake, DNA synthesis, and synthesis of phosphatidylcholine (Additional file 1 : Table S1) . Expression changes in GART were significantly correlated with chemosensitivity (Table 2 ), and as GART expression is associated with poor prognosis in several cancers [ 82 , 83 ], this might indicate a particular requirement for purine biosynthesis in response to drug treatment. None of the OCM genes satisfied the criteria for concerted upregulation; however, several genes, most notably MTHFS at 2 h after treatment , demonstrated a trend for upregulation among the majority of the cell lines (data not shown).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Concerted changes in transcriptional regulation of genes involved in DNA methylation, demethylation, and folate-mediated one-carbon metabolism pathways in the NCI-60 cancer cell line panel in response to cancer drug treatment

et al. 2016

View full text Add to dashboard Cite

BackgroundAberrant patterns of DNA methylation are abundant in cancer, and epigenetic pathways are increasingly being targeted in cancer drug treatment. Genetic components of the folate-mediated one-carbon metabolism pathway can affect DNA methylation and other vital cell functions, including DNA synthesis, amino acid biosynthesis, and cell growth.ResultsWe used a bioinformatics tool, the Transcriptional Pharmacology Workbench, to analyze temporal changes in gene expression among epigenetic regulators of DNA methylation and demethylation, and one-carbon metabolism genes in response to cancer drug treatment. We analyzed gene expression information from the NCI-60 cancer cell line panel after treatment with five antitumor agents, 5-azacytidine, doxorubicin, vorinostat, paclitaxel, and cisplatin. Each antitumor agent elicited concerted changes in gene expression of multiple pathway components across the cell lines. Expression changes of FOLR2, SMUG1, GART, GADD45A, MBD1, MTR, MTHFD1, and CTH were significantly correlated with chemosensitivity to some of the agents. Among many genes with concerted expression response to individual antitumor agents were genes encoding DNA methyltransferases DNMT1, DNMT3A, and DNMT3B, epigenetic and DNA repair factors MGMT, GADD45A, and MBD1, and one-carbon metabolism pathway members MTHFD1, TYMS, DHFR, MTR, MAT2A, SLC19A1, ATIC, and GART.ConclusionsThese transcriptional changes are likely to influence vital cellular functions of DNA methylation and demethylation, cellular growth, DNA biosynthesis, and DNA repair, and some of them may contribute to cytotoxic and apoptotic action of the drugs. This concerted molecular response was observed in a time-dependent manner, which may provide future guidelines for temporal selection of genetic drug targets for combination drug therapy treatment regimens.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0240-3) contains supplementary material, which is available to authorized users.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Concerted changes in transcriptional regulation of genes involved in DNA methylation, demethylation, and folate-mediated one-carbon metabolism pathways in the NCI-60 cancer cell line panel in response to cancer drug treatment

et al. 2016

View full text Add to dashboard Cite

show abstract

“…nucleotide synthesis) supporting DNA replication is required as cells enter and progress through S-phase [ 39 , 40 ]. Folate enzymes supporting nucleotide biosynthesis, a key pathway activated in rapidly proliferating cell, are commonly elevated in S-phase [ 41 – 45 ]. In contrast, ALDH1L1, which directly competes with the de novo purine biosynthesis for the same substrate, 10-formyl-THF, was downregulated ( Fig 1A and 1B ).…”

Section: Discussionmentioning

confidence: 99%

CHIP E3 ligase mediates proteasomal degradation of the proliferation regulatory protein ALDH1L1 during the transition of NIH3T3 fibroblasts from G0/G1 to S-phase

et al. 2018

View full text Add to dashboard Cite

ALDH1L1 is a folate-metabolizing enzyme abundant in liver and several other tissues. In human cancers and cell lines derived from malignant tumors, the ALDH1L1 gene is commonly silenced through the promoter methylation. It was suggested that ALDH1L1 limits proliferation capacity of the cell and thus functions as putative tumor suppressor. In contrast to cancer cells, mouse cell lines NIH3T3 and AML12 do express the ALDH1L1 protein. In the present study, we show that the levels of ALDH1L1 in these cell lines fluctuate throughout the cell cycle. During S-phase, ALDH1L1 is markedly down regulated at the protein level. As the cell cultures become confluent and cells experience increased contact inhibition, ALDH1L1 accumulates in the cells. In agreement with this finding, NIH3T3 cells arrested in G1/S-phase by a thymidine block completely lose the ALDH1L1 protein. Treatment with the proteasome inhibitor MG-132 prevents such loss in proliferating NIH3T3 cells, suggesting the proteasomal degradation of the ALDH1L1 protein. The co-localization of ALDH1L1 with proteasomes, demonstrated by confocal microscopy, supports this mechanism. We further show that ALDH1L1 interacts with the chaperone-dependent E3 ligase CHIP, which plays a key role in the ALDH1L1 ubiquitination and degradation. In NIH3T3 cells, silencing of CHIP by siRNA halts, while transient expression of CHIP promotes, the ALDH1L1 loss. The downregulation of ALDH1L1 is associated with the accumulation of the ALDH1L1 substrate 10-formyltetrahydrofolate, which is required for de novo purine biosynthesis, a key pathway activated in S-phase. Overall, our data indicate that CHIP-mediated proteasomal degradation of ALDH1L1 facilitates cellular proliferation.

show abstract

“…Their frequent somatic inactivation in MSI CRC can impede the progress of cell transformation and lead to the regression of clones in which they occur. A major example of this was WNK1 , which codes for a positive regulator of canonical Wnt/-catenin signaling and whose inactivation in different tumor types is deleterious, 38 , 39 other mutations occurring in HMGXB4 , GART , 40 , 41 RFC3 , 42 , 43 or PRRC2C , and the silencing of this latter candidate decreased cell proliferation in lung cancer. 44 In line with our results, a recent study also found that silencing of some of these targets ( WNK1 , RFC3 , and GART ) was lethal in haploid human tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Identification of Positively and Negatively Selected Driver Gene Mutations Associated With Colorectal Cancer With Microsatellite Instability

Jonchère

Marisa

Greene

et al. 2018

Cellular and Molecular Gastroenterology and Hepatology

View full text Add to dashboard Cite

Background & AimsRecent studies have shown that cancers arise as a result of the positive selection of driver somatic events in tumor DNA, with negative selection playing only a minor role, if any. However, these investigations were concerned with alterations at nonrepetitive sequences and did not take into account mutations in repetitive sequences that have very high pathophysiological relevance in the tumors showing microsatellite instability (MSI) resulting from mismatch repair deficiency investigated in the present study.MethodsWe performed whole-exome sequencing of 47 MSI colorectal cancers (CRCs) and confirmed results in an independent cohort of 53 MSI CRCs. We used a probabilistic model of mutational events within microsatellites, while adapting pre-existing models to analyze nonrepetitive DNA sequences. Negatively selected coding alterations in MSI CRCs were investigated for their functional and clinical impact in CRC cell lines and in a third cohort of 164 MSI CRC patients.ResultsBoth positive and negative selection of somatic mutations in DNA repeats was observed, leading us to identify the expected true driver genes associated with the MSI-driven tumorigenic process. Several coding negatively selected MSI-related mutational events (n = 5) were shown to have deleterious effects on tumor cells. In the tumors in which deleterious MSI mutations were observed despite the negative selection, they were associated with worse survival in MSI CRC patients (hazard ratio, 3; 95% CI, 1.1–7.9; P = .03), suggesting their anticancer impact should be offset by other as yet unknown oncogenic processes that contribute to a poor prognosis.ConclusionsThe present results identify the positive and negative driver somatic mutations acting in MSI-driven tumorigenesis, suggesting that genomic instability in MSI CRC plays a dual role in achieving tumor cell transformation. Exome sequencing data have been deposited in the European genome–phenome archive (accession: EGAS00001002477).

show abstract

Increased expression of glycinamide ribonucleotide transformylase is associated with a poor prognosis in hepatocellular carcinoma, and it promotes liver cancer cell proliferation

Cited by 25 publications

References 26 publications

Concerted changes in transcriptional regulation of genes involved in DNA methylation, demethylation, and folate-mediated one-carbon metabolism pathways in the NCI-60 cancer cell line panel in response to cancer drug treatment

Concerted changes in transcriptional regulation of genes involved in DNA methylation, demethylation, and folate-mediated one-carbon metabolism pathways in the NCI-60 cancer cell line panel in response to cancer drug treatment

CHIP E3 ligase mediates proteasomal degradation of the proliferation regulatory protein ALDH1L1 during the transition of NIH3T3 fibroblasts from G0/G1 to S-phase

Identification of Positively and Negatively Selected Driver Gene Mutations Associated With Colorectal Cancer With Microsatellite Instability

Contact Info

Product

Resources

About